Australian Government Advances Stroke Research Targeting Neuroinflammation

Australian Government Advances Stroke Research Targeting Neuroinflammation

News

On 6 October 2018, the Hon Greg Hunt MP, Minister for Health, Australia, announced that the Australian Government will invest $1 million to improve recovery and rehabilitation and help stroke survivors back to work [1]. This funding includes $750,000 specifically designated for funding a clinical trial of the emerging, innovative perispinal etanercept (“PSE”) treatment for chronic stroke, developed in the U.S. [2, 3]. The Australian government’s announcement stated that “Perispinal Etanercept has been used in the United States to treat chronic stroke and brain injury in selected patients …. The treatment is predicted to reduce inflammation in the brain and therefore stroke’s impact.”

The Significance

This is the first official national governmental announcement recognizing and funding study of a treatment approach specifically targeting TNF for chronic stroke, i.e. neurological dysfunction lasting months or years after stroke. For centuries, chronic brain injury due to stroke was thought irreversible. It was only in 2011, when the first peer-reviewed case reports documenting rapid neurological improvement in chronic stroke patients within minutes of PSE administration were published, that this dogma was challenged [4].

Subsequently, in 2012, a peer-reviewed observational study involving 617 consecutive patients with chronic stroke treated with PSE documented statistically significant improvements in motor impairment, spasticity, sensory impairment, cognition, psychological/behavioral function, aphasia and pain [2].

Australian Government Advances Stroke Research

Figure 1: PET image of a living rat brain minutes after PSE demonstrating delivery of radiolabeled etanercept into the choroid plexus and cerebral ventricles. From Tobinick, E.L., K. Chen, and X. Chen, Rapid intracerebroventricular delivery of Cu-DOTA-etanercept after peripheral administration demonstrated by PET imaging. BMC Res Notes, 2009. 2: p. 28.

The underlying scientific rationale for this treatment modality is neutralization of excess levels of brain tumor necrosis factor (“TNF”) and reduction of chronic microgllal activation, to re-activate brain circuits made dormant by stroke-induced neuroinflammation [3-8].

This scientific rationale, and the plausibility of targeting chronic neuroinflammation for treatment of chronic stroke, was supported by the subsequent preliminary results of surgical implantation of modified mesenchymal stem cells in stroke, first shown clinically feasible in 2016 [8].

Perispinal etanercept

Etanercept is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton TNF receptor linked to the Fc portion of human IgG1.

Etanercept selectively binds to TNF and thereby reduces its biological activity. Perispinal administration, overlying the posterior neck, introduces etanercept into the area drained by the external vertebral venous plexus, enabling etanercept to be delivered into the cerebrospinal venous system [9-12].

Perispinal administration of etanercept is an off-label treatment method that has potential therapeutic utility for a variety of neuroinflammatory disorders [2, 3, 11-17]. Randomized, double-blind placebo-controlled trials are necessary to achieve regulatory funding of new drug treatments. Translational barriers in neuroinflammation research and treatment are considerable [8]. The Australian governmental funding of perispinal etanercept for chronic stroke is an important step in achieving widespread recognition of the potential of targeting excess TNF for treatment of neurological disorders.

Non-standard abbreviations
“PSE” for “perispinal etanercept”

Author Affiliation

Author: Edward Tobinick MD, Director, Institute of Neurological Recovery; Boca Raton, FL, USA; Contact information: nrimed@gmail.com Telephone: 561.353.9707; Fax: 561.372.7874


Disclosure
The author is the inventor of issued U.S., Canadian, European and Australian patents claiming methods of use of etanercept, including perispinal administration, for treatment of neurological disorders, and receives royalties pursuant to those patents. He is also the Director of the Institute of Neurological Recovery, a private medical practice that utilizes PSE for treatment of neuroinflammatory disorders.


References

  1. Hunt, G., $1 million to support the rehabilitation of stroke survivors. health.gov.au/internet/ministers/publishing.nsf/Content/health-mediarel-yr2018-hunt134.htm. 2018.
  2. Tobinick, E., N.M. Kim, G. Reyzin, H. Rodriguez-Romanacce, and V. DePuy, Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept. CNS Drugs, 2012. 26(12): p. 1051-70.
  3. Tobinick, E., Perispinal etanercept advances as a neurotherapeutic. Expert Rev Neurother, 2018. 18(6): p. 453-455.
  4. Tobinick, E., Rapid improvement of chronic stroke deficits after perispinal etanercept: three consecutive cases. CNS Drugs, 2011. 25(2): p. 145-55.
  5. Ignatowski, T.A., R.N. Spengler, K.M. Dhandapani, H. Folkersma, R.F. Butterworth, and E. Tobinick, Perispinal etanercept for post-stroke neurological and cognitive dysfunction: scientific rationale and current evidence. CNS Drugs, 2014. 28(8): p. 679-97.
  6. Spengler, R., An Evolving Concept: The Pathologic Level of Brain TNF is a Therapeutic Target for Chronic Pain Treatment. brainimmune.com/pathologic-level-brain-tnf-therapeutic-target-chronic-pain/. 2018.
  7. Grace, P., Microglia: gatekeepers for neuropathic pain. brainimmune.com/microglia-gatekeepers-for-neuropathic-pain/. 2018.
  8. Clark, I.A., Letter by Clark Regarding Article, “Clinical Outcomes of Transplanted Modified Bone Marrow-Derived Mesenchymal Stem Cells in Stroke: A Phase 1/2a Study”. Stroke, 2016. 47(12): p. e268.
  9. Tobinick, E., The cerebrospinal venous system: anatomy, physiology, and clinical implications. MedGenMed, 2006. 8(1): p. 53.
  10. Tobinick, E.L., K. Chen, and X. Chen, Rapid intracerebroventricular delivery of Cu-DOTA-etanercept after peripheral administration demonstrated by PET imaging. BMC Res Notes, 2009. 2: p. 28.
  11. Tobinick, E., Perispinal etanercept: a new therapeutic paradigm in neurology. Expert Rev Neurother, 2010. 10(6): p. 985-1002.
  12. Tobinick, E.L., Perispinal Delivery of CNS Drugs. CNS Drugs, 2016. 30(6): p. 469-80.
  13. Winkelstein, B.A., K.D. Allen, and L.A. Setton, Chapter 19: Intervertebral Disc Herniation: Pathophysiology and Emerging Therapies, in The Intervertebral Disc, I.M. Shapiro and M.V. Risbud, Editors. 2014, Springer-Verlag: Wien, Austria.
  14. Clark, I.A. and B. Vissel, A Neurologist’s Guide to TNF Biology and to the Principles behind the Therapeutic Removal of Excess TNF in Disease. Neural Plast, 2015: p. 358263.
  15. Bergold, P.J., Treatment of traumatic brain injury with anti-inflammatory drugs. Exp Neurol, 2016. 275 Pt 3: p. 367-80.
  16. Tobinick, E., H. Rodriguez-Romanacce, R. Kinssies, and N.M. Kim, Chapter 7 – Perispinal Etanercept for Traumatic Brain Injury, in New Therapeutics for Traumatic Brain Injury, K.A. Heidenreich, Editor. 2017, Academic Press/Elsevier: New York.
  17. Tobinick, E., Perispinal Delivery of CNS Drugs: From Corning to Perispinal Etanercept, brainimmune.com/perispinal-delivery-cns-drugs-corning-perispinal-etanercept/. 2016.

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